Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo

Jonathan A Fallowfield; Annette L Hayden; Victoria K Snowdon; Rebecca L Aucott; Ben M Stutchfield; Damian J Mole; Antonella Pellicoro; Timothy T Gordon-Walker; Alexander Henke; Joerg Schrader; Palak J Trivedi; Marc Princivalle; Stuart J Forbes; Jane E Collins; John P Iredale

doi:10.1002/hep.26627

Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo

Jonathan A Fallowfield, Annette L Hayden, Victoria K Snowdon, Rebecca L Aucott, Ben M Stutchfield, Damian J Mole, Antonella Pellicoro, Timothy T Gordon-Walker, Alexander Henke, Joerg Schrader, Palak J Trivedi, Marc Princivalle, Stuart J Forbes, Jane E Collins, John P Iredale

Immunology and Immunotherapy

Research output: Contribution to journal › Article › peer-review

62 Citations (Scopus)

Abstract

Active myofibroblast (MF) contraction contributes significantly to the increased intrahepatic vascular resistance that is the primary cause of portal hypertension (PHT) in cirrhosis. We sought proof of concept for direct therapeutic targeting of the dynamic component of PHT and markers of MF activation using short-term administration of the peptide hormone relaxin (RLN). We defined the portal hypotensive effect in rat models of sinusoidal PHT and the expression, activity, and function of the RLN-receptor signaling axis in human liver MFs. The effects of RLN were studied after 8 and 16 weeks carbon tetrachloride intoxication, following bile duct ligation, and in tissue culture models. Hemodynamic changes were analyzed by direct cannulation, perivascular flowprobe, indocyanine green imaging, and functional magnetic resonance imaging. Serum and hepatic nitric oxide (NO) levels were determined by immunoassay. Hepatic inflammation was assessed by histology and serum markers and fibrosis by collagen proportionate area. Gene expression was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting and hepatic stellate cell (HSC)-MF contractility by gel contraction assay. Increased expression of RLN receptor (RXFP1) was shown in HSC-MFs and fibrotic liver diseases in both rats and humans. RLN induced a selective and significant reduction in portal pressure in pathologically distinct PHT models, through augmentation of intrahepatic NO signaling and a dramatic reduction in contractile filament expression in HSC-MFs. Critical for translation, RLN did not induce systemic hypotension even in advanced cirrhosis models. Portal blood flow and hepatic oxygenation were increased by RLN in early cirrhosis. Treatment of human HSC-MFs with RLN inhibited contractility and induced an antifibrogenic phenotype in an RXFP1-dependent manner.

CONCLUSION: We identified RXFP1 as a potential new therapeutic target for PHT and MF activation status.

Original language	English
Pages (from-to)	1492-504
Number of pages	13
Journal	Hepatology
Volume	59
Issue number	4
Early online date	19 Jul 2013
DOIs	https://doi.org/10.1002/hep.26627
Publication status	Published - 1 Apr 2014

Keywords

Actins
Animals
Carbon Tetrachloride
Cells, Cultured
Desmin
Disease Models, Animal
Glial Fibrillary Acidic Protein
Hemodynamics
Humans
Hypertension, Portal
Liver
Liver Cirrhosis
Male
Myofibroblasts
Nitric Oxide
Rats
Rats, Sprague-Dawley
Receptors, G-Protein-Coupled
Receptors, Peptide
Relaxin

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Fallowfield, J. A., Hayden, A. L., Snowdon, V. K., Aucott, R. L., Stutchfield, B. M., Mole, D. J., Pellicoro, A., Gordon-Walker, T. T., Henke, A., Schrader, J., Trivedi, P. J., Princivalle, M., Forbes, S. J., Collins, J. E., & Iredale, J. P. (2014). Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo. Hepatology, 59(4), 1492-504. Advance online publication. https://doi.org/10.1002/hep.26627

@article{aca5e9ed17424cdfbb4b1ddfcee32694,

title = "Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo",

abstract = "Active myofibroblast (MF) contraction contributes significantly to the increased intrahepatic vascular resistance that is the primary cause of portal hypertension (PHT) in cirrhosis. We sought proof of concept for direct therapeutic targeting of the dynamic component of PHT and markers of MF activation using short-term administration of the peptide hormone relaxin (RLN). We defined the portal hypotensive effect in rat models of sinusoidal PHT and the expression, activity, and function of the RLN-receptor signaling axis in human liver MFs. The effects of RLN were studied after 8 and 16 weeks carbon tetrachloride intoxication, following bile duct ligation, and in tissue culture models. Hemodynamic changes were analyzed by direct cannulation, perivascular flowprobe, indocyanine green imaging, and functional magnetic resonance imaging. Serum and hepatic nitric oxide (NO) levels were determined by immunoassay. Hepatic inflammation was assessed by histology and serum markers and fibrosis by collagen proportionate area. Gene expression was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting and hepatic stellate cell (HSC)-MF contractility by gel contraction assay. Increased expression of RLN receptor (RXFP1) was shown in HSC-MFs and fibrotic liver diseases in both rats and humans. RLN induced a selective and significant reduction in portal pressure in pathologically distinct PHT models, through augmentation of intrahepatic NO signaling and a dramatic reduction in contractile filament expression in HSC-MFs. Critical for translation, RLN did not induce systemic hypotension even in advanced cirrhosis models. Portal blood flow and hepatic oxygenation were increased by RLN in early cirrhosis. Treatment of human HSC-MFs with RLN inhibited contractility and induced an antifibrogenic phenotype in an RXFP1-dependent manner.CONCLUSION: We identified RXFP1 as a potential new therapeutic target for PHT and MF activation status.",

keywords = "Actins, Animals, Carbon Tetrachloride, Cells, Cultured, Desmin, Disease Models, Animal, Glial Fibrillary Acidic Protein, Hemodynamics, Humans, Hypertension, Portal, Liver, Liver Cirrhosis, Male, Myofibroblasts, Nitric Oxide, Rats, Rats, Sprague-Dawley, Receptors, G-Protein-Coupled, Receptors, Peptide, Relaxin",

author = "Fallowfield, {Jonathan A} and Hayden, {Annette L} and Snowdon, {Victoria K} and Aucott, {Rebecca L} and Stutchfield, {Ben M} and Mole, {Damian J} and Antonella Pellicoro and Gordon-Walker, {Timothy T} and Alexander Henke and Joerg Schrader and Trivedi, {Palak J} and Marc Princivalle and Forbes, {Stuart J} and Collins, {Jane E} and Iredale, {John P}",

note = "Copyright {\textcopyright} 2014 by the American Association for the Study of Liver Diseases.",

year = "2014",

month = apr,

day = "1",

doi = "10.1002/hep.26627",

language = "English",

volume = "59",

pages = "1492--504",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Wiley",

number = "4",

}

Fallowfield, JA, Hayden, AL, Snowdon, VK, Aucott, RL, Stutchfield, BM, Mole, DJ, Pellicoro, A, Gordon-Walker, TT, Henke, A, Schrader, J, Trivedi, PJ, Princivalle, M, Forbes, SJ, Collins, JE & Iredale, JP 2014, 'Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo', Hepatology, vol. 59, no. 4, pp. 1492-504. https://doi.org/10.1002/hep.26627

TY - JOUR

T1 - Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo

AU - Fallowfield, Jonathan A

AU - Hayden, Annette L

AU - Snowdon, Victoria K

AU - Aucott, Rebecca L

AU - Stutchfield, Ben M

AU - Mole, Damian J

AU - Pellicoro, Antonella

AU - Gordon-Walker, Timothy T

AU - Henke, Alexander

AU - Schrader, Joerg

AU - Trivedi, Palak J

AU - Princivalle, Marc

AU - Forbes, Stuart J

AU - Collins, Jane E

AU - Iredale, John P

PY - 2014/4/1

Y1 - 2014/4/1

N2 - Active myofibroblast (MF) contraction contributes significantly to the increased intrahepatic vascular resistance that is the primary cause of portal hypertension (PHT) in cirrhosis. We sought proof of concept for direct therapeutic targeting of the dynamic component of PHT and markers of MF activation using short-term administration of the peptide hormone relaxin (RLN). We defined the portal hypotensive effect in rat models of sinusoidal PHT and the expression, activity, and function of the RLN-receptor signaling axis in human liver MFs. The effects of RLN were studied after 8 and 16 weeks carbon tetrachloride intoxication, following bile duct ligation, and in tissue culture models. Hemodynamic changes were analyzed by direct cannulation, perivascular flowprobe, indocyanine green imaging, and functional magnetic resonance imaging. Serum and hepatic nitric oxide (NO) levels were determined by immunoassay. Hepatic inflammation was assessed by histology and serum markers and fibrosis by collagen proportionate area. Gene expression was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting and hepatic stellate cell (HSC)-MF contractility by gel contraction assay. Increased expression of RLN receptor (RXFP1) was shown in HSC-MFs and fibrotic liver diseases in both rats and humans. RLN induced a selective and significant reduction in portal pressure in pathologically distinct PHT models, through augmentation of intrahepatic NO signaling and a dramatic reduction in contractile filament expression in HSC-MFs. Critical for translation, RLN did not induce systemic hypotension even in advanced cirrhosis models. Portal blood flow and hepatic oxygenation were increased by RLN in early cirrhosis. Treatment of human HSC-MFs with RLN inhibited contractility and induced an antifibrogenic phenotype in an RXFP1-dependent manner.CONCLUSION: We identified RXFP1 as a potential new therapeutic target for PHT and MF activation status.

AB - Active myofibroblast (MF) contraction contributes significantly to the increased intrahepatic vascular resistance that is the primary cause of portal hypertension (PHT) in cirrhosis. We sought proof of concept for direct therapeutic targeting of the dynamic component of PHT and markers of MF activation using short-term administration of the peptide hormone relaxin (RLN). We defined the portal hypotensive effect in rat models of sinusoidal PHT and the expression, activity, and function of the RLN-receptor signaling axis in human liver MFs. The effects of RLN were studied after 8 and 16 weeks carbon tetrachloride intoxication, following bile duct ligation, and in tissue culture models. Hemodynamic changes were analyzed by direct cannulation, perivascular flowprobe, indocyanine green imaging, and functional magnetic resonance imaging. Serum and hepatic nitric oxide (NO) levels were determined by immunoassay. Hepatic inflammation was assessed by histology and serum markers and fibrosis by collagen proportionate area. Gene expression was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting and hepatic stellate cell (HSC)-MF contractility by gel contraction assay. Increased expression of RLN receptor (RXFP1) was shown in HSC-MFs and fibrotic liver diseases in both rats and humans. RLN induced a selective and significant reduction in portal pressure in pathologically distinct PHT models, through augmentation of intrahepatic NO signaling and a dramatic reduction in contractile filament expression in HSC-MFs. Critical for translation, RLN did not induce systemic hypotension even in advanced cirrhosis models. Portal blood flow and hepatic oxygenation were increased by RLN in early cirrhosis. Treatment of human HSC-MFs with RLN inhibited contractility and induced an antifibrogenic phenotype in an RXFP1-dependent manner.CONCLUSION: We identified RXFP1 as a potential new therapeutic target for PHT and MF activation status.

KW - Actins

KW - Animals

KW - Carbon Tetrachloride

KW - Cells, Cultured

KW - Desmin

KW - Disease Models, Animal

KW - Glial Fibrillary Acidic Protein

KW - Hemodynamics

KW - Humans

KW - Hypertension, Portal

KW - Liver

KW - Liver Cirrhosis

KW - Male

KW - Myofibroblasts

KW - Nitric Oxide

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptors, G-Protein-Coupled

KW - Receptors, Peptide

KW - Relaxin

U2 - 10.1002/hep.26627

DO - 10.1002/hep.26627

M3 - Article

C2 - 23873655

SN - 0270-9139

VL - 59

SP - 1492

EP - 1504

JO - Hepatology

JF - Hepatology

IS - 4

ER -

Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo

Abstract

Keywords

UN SDGs

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